Recent estimates indicate that more than 19 million Americans over the age of 18 years experience a depressive illness each year. It has been generally believed that there is some form of association between folate-deficiency states and depression [1, 2 and 3], which in turn helps to explain prior observations on the myriad neuropsychiatric presentations of megaloblastic anemia [4]. Recently, the relevance of folate in other medical conditions, in particular neural tube defects [5] and cardiovascular disease, [6] and potential antidepressant efficacy of agents marketed as dietary supplements or “nutraceuticals,” [7 and 8] such as S-adenosyl-methionine (SAMe), hypericum perforatum (St. John's wort), and omega-3-fatty acids, has been increasingly recognized. The field has gradually moved toward researching the impact of folate deficiency, replacement, and supplementation on the course and management of depressive disorders, in particular major depressive disorder, [9] and putative roles of folate in central-nervous-system function. [10, 11 and 12]. While significant advances in the treatment of depression have been made in the past decade, as many as 29% to 46% of patients with depression taking an anti-depressant are still partially or totally resistant to the treatment. Those who suffer from treatment-resistant depression have almost no alternatives. As not every treatment regimen is effective for each individual, there is a strong need to identify markers that can facilitate selection of an appropriate treatment regimen for a subject with depression.